Ischemic stroke is sudden neurologic deficits that result from focal cerebral ischemia associated with permanent brain infarction (eg, positive results on diffusion-weighted MRI). Common causes are (from most to least common) atherothrombotic occlusion of large arteries; cerebral embolism (embolic infarction); nonthrombotic occlusion of small, deep cerebral arteries (lacunar infarction); and proximal arterial stenosis with hypotension that decreases cerebral blood flow in arterial watershed zones (hemodynamic stroke). Diagnosis is clinical, but CT or MRI is done to exclude hemorrhage and confirm the presence and extent of stroke. Thrombolytic therapy may be useful acutely in certain patients. Depending on the cause of stroke, carotid endarterectomy or stenting, antiplatelet drugs, or warfarin may help reduce risk of subsequent strokes.
The following are the modifiable risk factors that contribute the most to increased risk of ischemic stroke:
Unmodifiable risk factors include the following:
Ischemia usually results from thrombi or emboli. Even infarcts classified as lacunar based on clinical criteria (morphology, size, and location) often involve small thrombi or emboli.
Atherothrombotic occlusion of large arteries (thrombus superimposed on an atherosclerotic artery) is the most common cause of ischemic stroke.
Atheromas, particularly if ulcerated, predispose to thrombi. Atheromas can occur in any major cerebral artery and are common at areas of turbulent flow, particularly at the carotid bifurcation. Partial or complete thrombotic occlusion occurs most often at the main trunk of the middle cerebral artery and its branches but is also common in the large arteries at the base of the brain, in deep perforating arteries, and in small cortical branches. The basilar artery and the segment of the internal carotid artery between the cavernous sinus and supraclinoid process are often occluded.
Less common causes of thrombosis include vascular inflammation secondary to disorders such as acute or chronic meningitis, vasculitic disorders, and syphilis; dissection of intracranial arteries or the aorta; hypercoagulability disorders (eg, antiphospholipid syndrome, hyperhomocysteinemia); hyperviscosity disorders (eg, polycythemia, thrombocytosis, hemoglobinopathies, plasma cell disorders); and rare disorders (eg, fibromuscular dysplasia, moyamoya disease, Binswanger disease). Older oral contraceptive formulations increase risk of thrombosis. In children, sickle cell disease is a common cause of ischemic stroke.
Emboli may lodge anywhere in the cerebral arterial tree.
Emboli may originate as cardiac thrombi, especially in the following conditions:
Other sources include clots that form after open-heart surgery and atheromas in neck arteries or in the aortic arch. Rarely, emboli consist of fat (from fractured long bones), air (in decompression sickness), or venous clots that pass from the right to the left side of the heart through a patent foramen ovale with shunt (paradoxical emboli). Emboli may dislodge spontaneously or after invasive cardiovascular procedures (eg, catheterization). Rarely, thrombosis of the subclavian artery results in embolic stroke in the vertebral artery or its branches.
Ischemic stroke can also result from lacunar infarcts. These small (≤ 1.5 cm) infarcts result from nonatherothrombotic obstruction of small, perforating arteries that supply deep cortical structures; the usual cause is lipohyalinosis (degeneration of the media of small arteries and replacement by lipids and collagen). Whether emboli cause lacunar infarcts is controversial. Lacunar infarcts tend to occur in elderly patients with diabetes or poorly controlled hypertension.
Any factor that impairs systemic perfusion (eg, carbon monoxide toxicity, severe anemia or hypoxia, polycythemia, hypotension) increases risk of all types of ischemic strokes. A stroke may occur along the borders between territories of arteries (watershed areas); in such areas, blood supply is normally low, particularly if patients have hypotension and/or if major cerebral arteries are stenotic.
Less commonly, ischemic stroke results from vasospasm (eg, during migraine, after subarachnoid hemorrhage, after use of sympathomimetic drugs such as cocaine or amphetamines) or venous sinus thrombosis (eg, during intracranial infection, postoperatively, peripartum, secondary to a hypercoagulability disorder).
Inadequate blood flow in a single brain artery can often be compensated for by an efficient collateral system, particularly between the carotid and vertebral arteries via anastomoses at the circle of Willis and, to a lesser extent, between major arteries supplying the cerebral hemispheres. However, normal variations in the circle of Willis and in the caliber of various collateral vessels, atherosclerosis, and other acquired arterial lesions can interfere with collateral flow, increasing the chance that blockage of one artery will cause brain ischemia.
Some neurons die when perfusion is < 5% of normal for > 5 min; however, the extent of damage depends on the severity of ischemia. If it is mild, damage proceeds slowly; thus, even if perfusion is 40% of normal, 3 to 6 h may elapse before brain tissue is completely lost. However, if severe ischemia (ie, decrease in perfusion) persists > 15 to 30 min, all of the affected tissue dies (infarction). Damage occurs more rapidly during hyperthermia and more slowly during hypothermia. If tissues are ischemic but not yet irreversibly damaged, promptly restoring blood flow may reduce or reverse injury. For example, intervention may be able to salvage the moderately ischemic areas (penumbras) that often surround areas of severe ischemia (these areas exist because of collateral flow).
Mechanisms of ischemic injury include edema, microvascular thrombosis, programmed cell death (apoptosis), and infarction with cell necrosis. Inflammatory mediators (eg, IL-1B, tumor necrosis factor-α) contribute to edema and microvascular thrombosis. Edema, if severe or extensive, can increase intracranial pressure. Many factors may contribute to necrotic cell death; they include loss of ATP stores, loss of ionic homeostasis (including intracellular Ca accumulation), lipid peroxidative damage to cell membranes by free radicals (an iron-mediated process), excitatory neurotoxins (eg, glutamate), and intracellular acidosis due to accumulation of lactate.
Symptoms and Signs
Symptoms and signs depend on the part of brain affected. Patterns of neurologic deficits often suggest the affected artery (see Table 1: Selected Stroke Syndromes), but correlation is often inexact.
Deficits may become maximal within several minutes of onset, typically in embolic stroke. Less often, deficits evolve slowly, usually over 24 to 48 h (called evolving stroke or stroke in evolution), typically in atherothrombotic stroke. In most evolving strokes, unilateral neurologic dysfunction (often beginning in one arm, then spreading ipsilaterally) extends without causing headache, pain, or fever. Progression is usually stepwise, interrupted by periods of stability. A stroke is considered submaximal when after it is complete, there is residual function in the affected area, suggesting viable tissue at risk of damage.
Embolic strokes often occur during the day; headache may precede neurologic deficits. Thrombi tend to occur during the night and thus are first noticed on awakening. Lacunar infarcts may produce one of the classic lacunar syndromes (eg, pure motor hemiparesis, pure sensory hemianesthesia, ataxic hemiparesis, dysarthria–clumsy hand syndrome); signs of cortical dysfunction (eg, aphasia) are absent. Multiple lacunar infarcts may result in multi-infarct dementia.
A seizure may occur at stroke onset, more often with embolic than thrombotic stroke. Seizures may also occur months to years later; late seizures result from scarring or hemosiderin deposition at the site of ischemia.
Deterioration during the first 48 to 72 h after onset of symptoms, particularly progressively impaired consciousness, results more often from cerebral edema than from extension of the infarct. Unless the infarct is large or extensive, function commonly improves within the first few days; further improvement occurs gradually for up to 1 yr.
Diagnosis is suggested by sudden neurologic deficits referable to a specific arterial territory. Ischemic stroke must be distinguished from other causes of similar focal deficits (eg, hypoglycemia; postictal [Todd] paralysis; hemorrhagic stroke; rarely, migraine), sometimes called stroke mimics. Headache, coma or stupor, and vomiting are more likely with hemorrhagic stroke.
Differentiating clinically between the types of stroke is imprecise; however, some clues based on symptom progression, time of onset, and type of deficit can help.
Although diagnosis is clinical, neuroimaging and bedside glucose testing are mandatory. CT is done first to exclude intracerebral hemorrhage, subdural or epidural hematoma, and a rapidly growing, bleeding, or suddenly symptomatic tumor. CT evidence of even a large anterior circulation ischemic stroke may be subtle during the first few hours; changes may include effacement of sulci or the insular cortical ribbon, loss of the gray-white junction between cortex and white matter, and a dense middle cerebral artery sign. Within 6 to 12 h of ischemia, medium-sized to large infarcts start to become visible as hypodensities; small infarcts (eg, lacunar infarcts) may be visible only with MRI. Diffusion-weighted MRI (highly sensitive for early ischemia) can be done immediately after initial CT neuroimaging.
Distinction between lacunar, embolic, and thrombotic stroke based on history, examination, and neuroimaging is not always reliable, so tests to identify common or treatable causes and risk factors for all of these types of strokes are routinely done. Patients should be evaluated for the following categories of causes and risk factors:
For cardiac causes, testing typically includes ECG, telemetry or Holter monitoring, serum troponin, and transthoracic or transesophageal echocardiography.
For vascular causes, testing may include magnetic resonance angiography (MRA), CT angiography (CTA), carotid and transcranial duplex ultrasonography, and conventional angiography. The choice and sequence of testing is individualized, based on clinical findings. MRA, CTA, and carotid ultrasonography all show the anterior circulation; however, MRA and CTA provide better images of the posterior circulation than carotid ultrasonography. MRA is generally preferred to CTA if patients can remain still during MRA (to avoid motion artifact).
For blood-related causes (eg, thrombotic disorders), blood tests are done to assess their contribution and that of other causes. Routine testing typically includes CBC, platelet count, PT/PTT, fasting blood glucose, and lipid profile.
Depending on which causes are clinically suspected, additional tests may include measurement of homocysteine, testing for thrombotic disorders (antiphospholipid antibodies, protein S, protein C, antithrombin III, factor V Leiden), testing for rheumatic disorders (eg, antinuclear antibodies, rheumatoid factor, ESR), syphilis serologic testing, Hb electrophoresis, and a urine drug screen for cocaine and amphetamines.
A cause cannot be identified for some strokes (cryptogenic strokes).
Stroke severity and progression are often assessed using standardized measures such as the National Institutes of Health (NIH) Stroke Scale (see Table 3: The National Institutes of Health Stroke Scale*); the score on this scale correlates with extent of functional impairment and prognosis. During the first days, progression and outcome can be difficult to predict. Older age, impaired consciousness, aphasia, and brain stem signs suggest a poor prognosis. Early improvement and younger age suggest a favorable prognosis.
About 50% of patients with moderate or severe hemiplegia and most with milder deficits have a clear sensorium and eventually can take care of their basic needs and walk adequately. Complete neurologic recovery occurs in about 10%. Use of the affected limb is usually limited, and most deficits that remain after 12 mo are permanent. Subsequent strokes often occur, and each tends to worsen neurologic function. About 20% of patients die in the hospital; mortality rate increases with age.
Guidelines for early management of stroke are available from the Stroke Council of the American Heart Association/American Stroke Association. Patients with acute ischemic strokes are usually hospitalized. Supportive measures (see Treatment) may be needed during initial evaluation and stabilization.
Perfusion of an ischemic brain area may require a high BP because autoregulation is lost; thus, BP should not be decreased except in the following cases:
To lower BP, clinicians can give nicardipine 2.5 mg/h IV initially; dose is increased by 2.5 mg/h q 5 min to a maximum of 15 mg/h as needed to decrease systolic BP by 10 to 15%. Alternatively, IV labetalol 20 mg IV can be given over 2 min; if response is inadequate, 40 to 80 mg can be given every 10 min up to a total dose of 300 mg.
Patients with presumed thrombi or emboli may be treated with tPA, thrombolysis-in-situ, antiplatelet drugs, and/or anticoagulants. Most patients are not candidates for thrombolytic therapy; they should be given an antiplatelet drug (usually aspirin 325 mg po) when they are admitted to the hospital. Contraindications to antiplatelet drugs include aspirin- or NSAID-induced asthma or urticaria, other hypersensitivity to aspirin or to tartrazine, acute GI bleeding, G6PD deficiency, and use of warfarin.
Recombinant tPA is used for patients with acute ischemic stroke up to 3 h after symptom onset if they have no contraindications to tPA (see Table 4: Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke). Some experts recommend using tPA up to 4.5 h after symptom onset (see Expansion of the Time Window for Treatment of Acute Ischemic Stroke With Intravenous Tissue Plasminogen Activator); however, between 3 h and 4.5 h after symptom onset, additional exclusion criteria apply (see Table 4: Exclusion Criteria for Use of Tissue Plasminogen Activator in Stroke). Although tPA can cause fatal or other symptomatic brain hemorrhage, patients treated with tPA strictly according to protocols still have a higher likelihood of functional neurologic recovery. Only physicians experienced in stroke management should use tPA to treat patients with acute stroke; inexperienced physicians are more likely to violate protocols, resulting in more brain hemorrhages and deaths. When tPA is given incorrectly (eg, when given despite the presence of exclusion criteria), risk of hemorrhage due to tPA is high mainly for patients who have had stroke; risk is low for patients who have had a stroke mimic. If experienced physicians are not available on site, consultation with an expert at a stroke center (including video evaluation of the patient [telemedicine]), if possible, may enable these physicians to use tPA. Because most poor outcomes result from failure to strictly adhere to the protocol, a checklist of inclusion and exclusion criteria should be used.
tPA must be given within 4.5 h of symptom onset—a difficult requirement. Because the precise time of symptom onset may not be known, clinicians must start timing from the moment the patient was last observed to be well.
Before treatment with tPA, brain hemorrhage must be excluded by CT, systolic BP must be < 185 mm Hg, and diastolic BP must be < 110 mm Hg; antihypertensive drugs (IV nicardipine, IV labetalol) may be given as above. Dose of tPA is 0.9 mg/kg IV (maximum dose 90 mg); 10% is given by rapid IV injection, and the remainder by constant infusion over 60 min. Vital signs are closely monitored for 24 h after treatment, and BP is maintained below 185 mm Hg systolic and 110 mm Hg diastolic. Any bleeding complications are aggressively managed. Anticoagulants and antiplatelet drugs are not used within 24 h of treatment with tPA.
Thrombolysis-in-situ (angiographically directed intra-arterial thrombolysis) of a thrombus or embolus can sometimes be used for major strokes if symptoms began >3 h but < 6 h ago, particularly for strokes due to large occlusions in the middle cerebral artery. Clots in the basilar artery may be intra-arterially lysed up to 12 h after stroke onset, sometimes even later depending on the clinical circumstances. This treatment, although standard of care in some large stroke centers, is often unavailable in other hospitals.
Mechanical thrombectomy (angiographically directed intra-arterial removal of a thrombus or embolus by a device) is often used as rescue treatment for patients who have had a severe stroke and have an NIH stroke score ≥ 8 when IV and/or intra-arterial thrombolysis has been ineffective; it must be done within 8 h of symptom onset. Mechanical thrombectomy may be part of standard of care in large stroke centers. It should not be used outside of a stroke center and should not be used instead of IV recombinant tPA within 4.5 h of onset of symptoms in eligible patients with acute ischemic stroke. Devices used to remove thrombi are being improved, and recent models reestablish perfusion in 90 to 100% of patients. It is unclear whether clinical outcomes are better after successful mechanical reperfusion than after treatment with IV tPA; evidence suggests that the earlier reperfusion is achieved, the better the outcome regardless how it is achieved.
In some stroke centers, IV tPA, thrombolysis in situ, and/or mechanical thrombectomy are sometimes done based on imaging criteria (tissue-based criteria) rather than on time after symptom onset (time-based criteria). Tissue-based criteria can be used when time of symptom onset cannot be established (eg, if a patient awakens with stroke symptoms after sleeping several hours or if a patient has aphasia and cannot provide a time frame). To determine eligibility, clinicians use imaging to identify potentially salvageable brain tissue (also called penumbral tissue). The volume of infarcted tissue identified by diffusion-weighted MRI is compared with the volume of at-risk underperfused tissue identified by perfusion-weighted MRI or CT. A sizeable mismatch between the volumes identified by diffusion-weighted and perfusion-weighted imaging suggests that substantial penumbral tissue may still be rescued, and thus thrombolysis and/or thrombectomy is indicated. However, time-based criteria are still used in clinical practice; studies to determine whether outcomes are better using tissue- or time-based criteria are ongoing.
Anticoagulation with heparin or low molecular weight heparin is used for stroke caused by cerebral venous thrombosis and is sometimes used for emboli due to atrial fibrillation and for stroke due to presumed progressive thrombosis if it continues to evolve despite use of antiplatelet drugs and cannot be treated any other way (eg, with tPA or invasive methods). In one large series, outcomes after treatment of basilar artery thrombosis with IV heparin plus IV tPA were as good as or better than those after treatment with endovascular therapies. Warfarin is begun simultaneously with heparin. Before anticoagulation, hemorrhage must be excluded by CT. Constant weight-based heparin infusion (Fig. 2: Weight-based heparin dosing.) is used to increase PTT to 1.5 to 2 times baseline values until warfarin has increased the INR to 2 to 3 (3 in hypercoagulable disorders). Because warfarin predisposes to bleeding and is continued after hospital discharge, its use should be restricted to patients who are likely to comply with dosage and monitoring requirements and who are not prone to falls.
Supportive care is continued during convalescence. Controlling hyperglycemia and fever can limit brain damage after stroke, leading to better functional outcomes.
Long-term management also focuses on prevention of recurrent stroke (secondary prevention). Modifiable risk factors (eg, hypertension, diabetes, smoking, alcoholism, dyslipidemia, obesity) are treated. Reducing systolic BP may be more effective when the target BP is < 120 mm Hg rather than the typical level (< 140 mm Hg).
Extracranial carotid endarterectomy or stenting is indicated for patients with recent nondisabling, submaximal stroke attributed to an ipsilateral carotid obstruction of 70 to 99% of the arterial lumen or to an ulcerated plaque if life expectancy is at least 5 yr. In other symptomatic patients (eg, patients with TIAs), endarterectomy or stenting with antiplatelet therapy is indicated for carotid obstruction of ≥ 60% with or without ulceration if life expectancy is at least 5 yr. These procedures should be done by surgeons and interventionists who have a successful record with the procedure (ie, morbidity and mortality rate of < 3%) in the hospital where it will be done. If carotid stenosis is asymptomatic, endarterectomy or stenting is beneficial only when done by very experienced surgeons or interventionists, and that benefit is likely to be small. For many patients, carotid stenting with an emboli-protection device (a type of filter) is preferred to endarterectomy, particularly if patients are < 70 yr and have a high surgical risk. Carotid endarterectomy and stenting are equally effective for stroke prevention. In the periprocedural period, MI is more likely after endarterectomy, and recurrent stroke is more likely after stenting.
Extracranial vertebral angioplasty and/or stenting can be used in certain patients with recurrent symptoms of vertebrobasilar ischemia despite optimal medical treatment and a vertebral artery obstruction of 50 to 99%.
Intracranial major artery angioplasty and/or stenting is considered investigational for patients with recurrent stroke or TIA symptoms despite optimal medical treatment and a 50 to 99% obstruction of a major intracranial artery.
Endovascular closure of a patent foramen ovale does not appear to be more effective for preventing strokes than medical management, but studies are ongoing.
Oral antiplatelet drugs are used to prevent subsequent noncardioembolic (atherothrombotic, lacunar, cryptogenic) strokes (secondary prevention). Aspirin 81 or 325 mg once/day, clopidogrel 75 mg once/day, or the combination product aspirin 25 mg/extended-release dipyridamole 200 mg bid may be used. In patients taking warfarin, antiplatelet drugs additively increase risk of bleeding and are thus usually avoided; however, aspirin is occasionally used simultaneously with warfarin in certain high-risk patients. Clopidogrel is indicated for patients who are allergic to aspirin. If ischemic stroke recurs or if a coronary artery stent becomes blocked while patients are taking clopidogrel, clinicians should suspect impaired metabolism of clopidogrel (ineffective conversion of clopidogrel to its active form because CYP2C19 activity is reduced); a test to determine CYP2C19 status (eg, genetic testing for CYP450 polymorphisms) is recommended. If impaired metabolism is confirmed, aspirin or the combination product aspirin/extended-release dipyridamole is a reasonable alternative. If patients have had a TIA or minor stroke, clopidogrel plus aspirin given within 24 h of symptom onset appears more effective than aspirin alone for reducing risk of stroke in the first 90 days and does not increase risk of hemorrhage. However, prolonged (eg, > 6 mo) use of clopidogrel plus aspirin is avoided because it has no advantage over aspirin alone in long-term secondary stroke prevention and results in more bleeding complications. Clopidogrel plus aspirin before and for ≥ 30 days after stenting is indicated, usually for ≤ 6 mo; if patients cannot tolerate clopidogrel, ticlopidine 250 mg bid can be substituted.
Oral anticoagulants are indicated for secondary prevention of cardioembolic strokes (as well as primary prevention). Adjusted-dose warfarin (a vitamin K antagonist) with a target INR of 2 to 3 is used for certain patients with nonvalvular or valvular atrial fibrillation. A target INR of 2.5 to 3.5 is used if patients have a mechanical prosthetic cardiac valve. Efficacious alternatives to warfarin for patients with nonvalvular atrial fibrillation include the following new anticoagulants:
The main advantage of these new anticoagulants is ease of use (eg, no need to check anticoagulation level with a blood test after the initial dose or to use a parenteral anticoagulant such as unfractionated heparin given by continuous infusion when transitioning from parenteral to oral anticoagulants). Their main disadvantage is lack of an antidote to reverse anticoagulation in case a hemorrhagic complication occurs. Efficacy and safety of combining any of these new anticoagulants with an antiplatelet drug have not been established.
Statins are used to prevent recurrent strokes; lipid levels must be decreased by substantial amounts. Atorvastatin 80 mg once/day is recommended for patients with evidence of atherosclerotic stroke and LDL (low-density lipoprotein) cholesterol ≥ 100 mg/dL. A reasonable LDL cholesterol target is a 50% reduction or a level of < 70 mg/dL. Other statins (eg, simvastatin, pravastatin) may be also used.
Last full review/revision November 2013 by Elias A. Giraldo, MD, MS
Content last modified November 2013